Our data, now confirmed by many groups, show that there are at least two classes of hematopoietic stem cells (HSC): primitive or high quality stem cells that are capable of producing life-ling engraftment of all hematologic lineages and committed or low quality stem cells that produce only short-term hematologic reconstitution. We found that high quality HSC do not produce assayable progenitors upon direct culture and are unable to produce rapid engraftment after transplantation; however, high quality HSC are capable of marked cellular expansion in vitro with the production of large numbers of progenitors. We hypothesize that the immune attack in severe aplastic anemia (SAA) is against low quality HSC, but spares high quality HSC. The persistence of high quality HSC in SAA would explain the success of high-dose cyclophosphamide without blood or marrow transplantation in this disease. Our preliminary data suggest that high quality HSC can be isolated, and expanded in vitro, from patients with SAA. The overall objective of this proposal is to study the biology of SAA with the plan to develop novel clinical treatments for the disease. Specifically, we plan to: 1) continue to study the biology of HSC in SAA, especially approaches that will allow their expansion in vitro; 2) investigate the immuno-pathophysiology of SAA; and 3) develop novel clinical trials, especially autologous HSC transplantation, for the patients with SAA and acute leukemia.